The use of intravascular fluid is among the most important measures in the prophylaxis and therapy of hypovolemia, irrespective of whether the hypovolemia results from the immediate loss of blood or body fluids (in acute bleedings, traumas, surgery, burns), from disturbed distribution between macro- and microcirculation (such as in sepsis), or from vasodilation (e.g., during the initiation of anesthesia). Infusions suitable for such indications are supposed to restore normovolemia and maintain the perfusion of vital organs and the peripheral blood flow. At the same time, the solutions must not stress the circulation excessively, and they must be possibly free from side effects. In this respect, all the currently available volume replacements have benefits and drawbacks. Although so-called crystalloid solutions (electrolyte solutions) are essentially free from immediate side effects, they ensure only a short-term or inadequate stabilization of the intravascular volume and the hemodynamics. In case of pronounced or persisting hypovolemia, they must be infused in excessive amounts because they do not exclusively remain in the intravascular compartment but quickly dissipate in the extravascular space. However, a fast flow-out into the extravascular space not only limits the circulation-filling effect of crystalloid solutions but also involves the risk of peripheral and pulmonary edemas. Apart from the vital threat which a lung edema can represent, it additionally leads to a deterioration of the nutritive oxygen supply, which is also affected by peripheral edemas.
In contrast, colloidal volume replacements, whether the colloids contained therein are of natural or synthetic origin, have a much more reliable effect. This is due to the fact that, because of their colloid-osmotic effect, they retain the supplied liquid longer in the circulation as compared to crystalloids and thus protect them from flowing out into the interstice. On the other hand, colloidal volume replacements cause a higher extent of undesirable responses as compared to crystalloid solutions. Thus, the natural colloid albumin, like all blood or plasma derivatives, involves the risk of infection with viral diseases; in addition, it may result in interactions with other drugs. e.g., ACE inhibitors; finally, the availability of albumin is limited, and its use as a volume replacement is disproportionately expensive. Further doubts as to the use of albumin as a volume replacement are due to the inhibition of the endogenous synthesis of albumin if it is added exogenously and due to its ready extravascularization. This means the passage from the circulation into the extravascular space, where undesirable and persistant liquid accumulations can occur because of the colloid-osmotic effect of albumin.
In the synthetic colloids, severe anaphylactoid responses and a massive inhibition of blood coagulation have caused dextran preparations to disappear almost completely from therapy. Although hydroxyethylstarch (HES) solutions also have the potential for triggering anaphylactoid responses and affecting blood coagulation, this is to a lesser extent as compared with dextran. Severe anaphylactoid responses (responses of severity III and IV) are observed extremely rarely with HES solutions, in contrast to dextran, and the influence on blood coagulation, inherent to the high-molecular weight HES solutions, could be significantly reduced in recent years by the further development of HES solutions. As compared with gelatin solutions, which also find use as plasma replacements and leave blood coagulation essentially unaffected, HES solutions, at least their high- and medium-molecular weight embodiments, have the benefit of a longer plasma residence time and effectiveness.
EP-A-0 402 724 discloses the preparation and use of a hydroxyethylstarch having an average molecular weight, Mw, of from 60,000 to 600,000, a molar substitution, MS, of from 0.15 to 0.5, and a degree of substitution. DS, of from 0.15 to 0.5. The disclosure deals with the rapid (6 to 12 hours) and complete degradability of the hydroxyethylstarches to be employed as plasma expanders. Within the preferred range of average molecular weights of from 100,000 to 300,000, a hydroxyethylstarch having an average molecular weight of 234,000 was explicitly examined.
U.S. Pat. No. 5,502,043 discloses the use of hydroxyethylstarches having an average molecular weight, Mw, of from 110,000 to 150,000, a molar substitution. MS, of from 0.38 to 0.5, and a degree of substitution. DS, of from 0.32 to 0.45 for improving microcirculation in peripheral arterial occlusive disease. In addition, the document teaches the use of low-molecular weight (Mw 110,000 to 150,000) hydroxyethylstarches which, due to their low molecular weight, keep the plasma viscosity low and thus ensure an improvement of microcirculation in the blood flow. However, this document advises against the use of higher-molecular weight hydroxyethylstarches, such as a hydroxyethylstarch with an Mw of 500,000, because they increase plasma viscosity and thus deteriorate microcirculation despite their low molar substitution (MS=0.28).
Worldwide, different HES preparations are currently used as colloidal volume replacements, which are mainly distinguished by their molecular weights and additionally by their extent of etherification with hydroxyethyl groups, and by other parameters. The best known representatives of this class of substances are the so-called Hetastarch (HES 450/0.7) and Pentastarch (HES 200/0.5). The latter is the currently most widespread “standard HES”. Besides, HES 200/0.62 and HES 70/0.5 play a minor role. The declared information relating to the molecular weight as well as that relating to the other parameters are averaged quantities, where the molecular weight declaration is based on the weight average (Mw) expressed in Daltons (e.g., for HES 200,000) or mostly abbreviated in Kilodaltons (e.g., for HES 200). The extent of etherification with hydroxyethyl groups is characterized by the molar substitution MS (e.g. as 0.5 such as in HES 200/0.5; MS=average molar ratio of hydroxyethyl groups to anhydroglucose units) or by the degree of substitution (DS=ratio of mono- or polyhydroxyethylated glucoses to the total anhydroglucose units). According to their molecular weights, the HES solutions in clinical use are classified into high-molecular weight (450 kD), medium-molecular weight (200-250 kD) and low-molecular weight (70-130 kD) preparations.
As to the coagulation effects of HES solutions, a distinction is to be made between non-specific and specific influences. A non-specific influence on blood coagulation results from dilution of the blood (hemodilution), which occurs during the infusion of HES solutions and other volume replacements into the circulation. Affected by this hemodilution are also coagulation factors, whose concentrations are decreased depending on the extent and duration of the dilution of the blood and the plasma proteins due to the infusion. Correspondingly large or persisting effects may result in a hypocoagulability which is detectable by laboratory diagnostics and, in extreme cases, clinically relevant.
In addition, hydroxyethylstarch may cause a specific influence on blood coagulation, for which several factors are held responsible. Thus, under certain conditions or with certain HES preparations, a decrease of the coagulation proteins factor VIII (F VIII) and von Willebrand factor (vWF) is found which is larger than the general decrease of the plasma proteins due to hemodilution. Whether this larger than expected decrease is caused by a reduced formation or release of F VIII/vWF, such as by coating effects on the vascular endothelium caused by HES, or by other mechanisms is not quite clear.
However, HES influences not only the concentration of the coagulation factors mentioned but evidently also the function of platelets. This is completely or in part due to the binding of HES to the surface of the platelets, which inhibits the access of ligands to the fibrinogen receptor of the platelets.
These specific effects of HES on blood coagulation are particularly pronounced when high-molecular weight HES (e.g. HES 450/0.7) are employed while they do not play such a great role for medium-molecular weight (e.g. HES 250/0.5) or low-molecular weight HES (e.g., HES 130/0.4 or HES 70/0.5) (J. Treib et al., Intensive Care Med. (1999), pp. 258 to 268; O. Langeron et al. Anesth. Analg. (2001), pp. 855 to 862; R. G. Strauss et al., Transfusion (1988), pp. 257-260; M. Jamnicki et al., Anesthesiology (2000), pp. 1231 to 1237).
If the risk profile of high-molecular weight HES is compared with that of the medium- and low-molecular weight preparations, a clear reduction of the risks can be established in the latter, i.e., not only with respect to the interaction with blood coagulation but also with respect to particular pharmacokinetic properties. Thus, the high-molecular weight HES solutions show a high accumulation in the circulation while this drawback is reduced in medium-molecular weight HES and virtually absent in low-molecular weight preparations. The fact that no more accumulation occurs with low-molecular weight HES solutions, such as HES 130/0.4, is a relevant therapeutic progress because the plasma levels of HES cannot be determined in clinical routine, and therefore, even extreme concentrations, which can be obtained within a few days with the high-molecular weight solutions, remain undiscovered. In this case, the amount of “residual HES” accumulated in the circulation is unknown to the user but it nevertheless influences the kinetics and behavior of the HES which was additively infused, not knowing the amounts still present in the circulation. Therefore, the effect of high-molecular weight HES according to the prior art is not calculable; it remains longer in the circulation than would be required or desired for therapeutic reasons in most cases, and its metabolic fate is unclear.
In contrast, low-molecular weight HES will disappear completely from the circulation within about 20 to 24 hours after the infusion. This avoids backlog effects, and no accumulation occurs, especially for repeated infusions. The pharmacokinetic behavior of low-molecular weight starch, in contrast to high-molecular weight starch, is calculable and therefore can be easily controlled. Too high a load on the circulation or the clearance mechanisms does not occur.
However, this behavior of low-molecular weight HES as compared to high-molecular weight preparations, which is advantageous as such, is purchased at the expense of a significantly shorter plasma half life. The plasma half life of low-molecular weight HES is only about half that of HES 200 or less (J. Waitzinger et al., Clin. Drug Invest. (1998), pp. 151 to 160) and is in the range of the half life of gelatin preparations, which are to be rated as decidedly short-term effective. Although a short half life of a volume replacement need not be categorically disadvantageous, because it can be compensated for by a more frequent or more highly dosed administration of the volume replacement in question, in severe or persisting hypovolemia, a volume replacement with a short half life and short effective period involves the risk of insufficient circulation filling (much like with crystalloid solutions) or, when the dosage is correspondingly increased for compensating for this drawback, the risk of interstitial liquid overload.